Regeneration, Remodeling, Regression: Vascular Biology Insights from the 3Rs of Botryllus schlosseri

The dysfunction of the vascular system underlies more than 70 diseases that affect over 1 billion people worldwide. The molecular, cellular, and developmental mechanisms that govern the vascular system can be categorized as the 3Rs of vascular biology: regeneration, remodeling, and regression. While the importance of the 3Rs in regulating homeostasis is widely accepted many aspects of the biological processes of the 3Rs are unknown or not well understood due to the experimental inaccessibility of vascular tissue in most organisms.;Here we investigate the 3Rs of vascular biology exhibited by the experimentally accessible and easily manipulated extracorporeal vasculature of the colonial ascidian Botryllus schlosseri. Ascidians such as Botryllus can be found in shallow waters and harbors throughout the world and are considered to be the closest non-vertebrate relatives to the vertebrates. Botryllus has been the focus of numerous genetic, developmental, and regenerative studies including studies of asexual development, stem cell parasitism, allorecognition, and angiogenesis. Using the unique biology of Botryllus we have further developed this animal as a novel model for vascular biology, deriving insights into all 3Rs of vascular biology.;Here we present our insights from the 3Rs of the Botryllus vasculature. Our insights into vascular regeneration include using a novel vascular cell lineage tracing methodology to assess regeneration in parabiosed individuals to demonstrate that the source of regenerated vasculature is due to the proliferation of pre-existing vascular resident cells and not a mobile progenitor (Chapter II). In our studies of remodeling we show that Botryllus expresses an orthologue of the angiogenic Tie receptor, not expressed in vasculature tissue but rather phagocytic cells involved in somatic tissue remodeling (Chapter III). Finally, we utilize the unique biology and experimental accessibility of Botryllus to investigate the role in which ECM modifying enzymes such as Lysyl Oxidase (LOX) play in maintaining vascular stability, demonstrating that inhibition of LOX allows for the induction of vascular regression (Chapter IV).;These insights will support future vascular biology studies and have established Botryllus as a model for the 3Rs of vascular biology.